The central nervous system (CNS), and in particular the brain, drives the cognitive functions. The cerebral cortex, which is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain, plays a key role in attention, perceptual awareness, thought, language, higher order cognition (executive function) and information integration of sensory input.
Central nervous system development and maturation is a highly complex biological phenomenon that involves a number of physiological processes including, for example, neuron and glial cell growth and differentiation, neuronal pathfinding and branching, and establishment of inter neuronal communication (nerve signals) via axon growth and neurotransmitter release. Furthermore, although not all axons are myelinated, myelination (an important function of glial cells) is necessary to insulate the electrical signal carried along the axons, thereby ensuring efficient signal transmission, and preventing cross talk between neighbouring nerves. [Baumann, N. and Pham-Dinh, D. (2001); Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System, Physiological Reviews, 81(2): 871-927]; [Deoni, S. C. et al. (2011); Mapping infant brain myelination with magnetic resonance imaging, J. Neurosci., 31(2): 784-91]. Myelination is partially regulated by Myelin Basic Protein.
Myelination begins during pregnancy and continues up until and during adolescence/early adulthood (until 20 years old) [Baumann, N. and Pham-Dinh, D. (2001)]; [Benton, D. (2010); Neurodevelopment and neurodegeneration: are there critical stages for nutritional intervention?, Nutr. Rev., 68 Suppl. 1: S6-10]. Myelination is one of the last brain developmental processes to take place and is one of the first to decline in aging. Thus, optimal myelination achieved early in life may limit its early decline.
Disrupted myelination during neuronal/brain development may contribute or worsen disorders such as autism, attention deficit/hyperactivity disorder and schizophrenia. Moreover, disorders associated with destruction of myelin insulation include multiple sclerosis, and, later in life, Alzheimer's disease.
Neuronal plasticity, which is defined as the ability of the brain to continuously adapt its functionally and structural organization to changing requirements is important in nervous system maturation. It is essential for the correct functioning of the brain and necessary for cognition, learning and memory. Some of the neuronal markers, including proteins and neurotrophic factors, like Brain Derived Neurotrophic Factor (BDNF) required for, or at least, associated with these physiological processes, have been identified in the literature and studied [Huang, E. J. and Reichardt, L. F. (2001); Neurotrophins: Roles in Neuronal Development and Function, Annu. Rev. Neurosci., 24: 677-736]; [Musumeci, G. and Minichiello, L. (2011); BDNF-TrkB signalling in fear learning: from genetics to neural networks, Rev. Neurosci., 22(3):303-15]; [Xiao, J. et al. (2009); The role of neurotrophins in the regulation of myelin development, Neurosignals, 17: 265-276] and [Von Bohlen and Halbach, 0. (2011); Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus, Cell Tissue Res., 345(1):1-19].
The central nervous system develops during gestation and then refines to a mature, functional network during the post natal period. In humans foetuses, the cerebral cortex develops quite late and over a protracted period of time.
In utero, there is a strong acceleration of neuronal/brain maturation and growth from week 30 of gestation in humans.
Premature babies show very basic electrical activity in the primary sensory regions of the cerebral cortex—those areas that perceive touch, vision, and hearing, as well as in primary motor regions of the cerebral cortex. These babies enter the world with a still-primitive cerebral cortex, and it is the gradual maturation of this complex part of the brain that explains much of their emotional, social and cognitive maturation in the first few years of life [Lubsen, J. et al. (2011); Microstructural and functional connectivity in the developing preterm brain, Seminars in Perinatology, 35, 34-43].
Preterm babies are born at a time that is crucial for structural and functional brain development and maturation and, so, they miss out on in utero brain development. They are at risk for medical conditions after birth, including hemorrhagic and hypoxic-ischemic brain injuries, as well as for development problems later in life, including cognitive deficits. This risk seems to be higher the younger the babies are delivered and the lower their birth weight is. Cognitive deficits in terms of lower IQ, lower attention and working memory abilities, and problems in executive functions may persist into school-age and adolescence [Talge, N. et al. (2010). Late-Preterm Birth and its Association with Cognitive and Socioemotional Outcomes at 6 Years of Age. Pediatrics, 126, 1124-1131; van Baar, A., et al. (2009). Functioning at school age of moderately preterm children born at 32 to 36 weeks' gestational age. Pediatrics, 124, 251-257; Farooqi, A et al. (2011). Impact at age 11 years of major neonatal morbidities in children born extremely preterm. Pediatrics, 127, e1247-1257; Nosarti, C. et al. (2010). Neurodevelopmental outcomes of preterm birth. Cambridge: Cambridge University Press].
Non-severe cases (low prematurity, for example, birth at 32 to <37 weeks; WHO, 2013, http://www.who.int/mediacentre/factsheets/fs363/en/) will likely “catch-up” their sub-optimal neuronal/brain maturation ex utero. However, because this maturation occurs in the presence of external stimuli (sounds, light, smell etc.) different from the in utero environment and the occurrence of brain damage due to prematurity, this “catch-up” brain maturation may be impacted, compared to that occurring in utero. The infant may experience difficulties in processing external information at the premature stage. This early setback in brain development carries the risk of sub-optimal cognitive abilities during the infant's subsequent development.
For the reasons outlined above, in severely premature infants (including extremely preterm infants, born at less than 28 weeks, and very preterm infants born between 28 and 32 weeks) the incidence of sub-normal cognitive function is more marked.
More generally CNS immaturity or delayed maturation of the CNS, can be observed in infants such as:                Preterm infants, low birth weight (<2500 g), very low and extremely low birth weight infants (<1500 g), extremely low birth weight (<1000 g) and in small for gestational age infants [Allen, M. C. (2008); Neurodevelopmental outcomes of preterm infants, Curr. Opin Neurol., 21(2): 123-8].        Premature or term-born infants having experienced an intrauterine growth retardation (IUGR) that occurred following any adverse events during the gestation (smoking of the mother, medication of the mother, low placenta quality, abnormal placenta positioning, malnutrition of the mother and the foetus, excessive stress/anxiety of the mother, etc); [Gregory, A. et al. (2008); Intrauterine Growth Restriction Affects the Preterm Infant's Hippocampus, Pediatric Research, 63(4): 438-443].        Any neonate and young infant showing nervous system growth retardation following, for example, hypoxemia-ischemia at birth, postnatal complications, postnatal steroid treatments or any other adverse event [Barrett, R. D. et al. (2007); Destruction and reconstruction: hypoxia and the developing brain, Birth Defects Res. C. Embryo Today, 81: 163-76].        
Cognitive dysfunctions are reported in these infants, along with dysfunction in their growth and development, indicating that an optimal “catch-up” of the neurodevelopmental process is not achieved.
Immaturity or delayed maturation of the cerebral cortex can lead to delayed and/or impaired learning ability, information integration, processing of sensory input, loss of, or poor development of higher reasoning, executive functions, concentration, attention, motor skills and language. This may lead to behavioral problems abnormally low intelligence, and thus, abnormally low mental performance.
Behavioral and neurodevelopmental disorders associated with delayed maturation of the cerebral cortex include attention deficit/hyperactivity disorders and autism spectrum disorders.
Thus, if the foetus, neonate or infant has experienced central nervous system growth retardation, it is desirable that this retardation be reversed quickly, and that any further retardation be prevented, so that the central nervous system development “catches up” to a normal level and that the growing foetus or infant experiences minimal cognitive function impairment later in life.
Cognitive function may be measured in humans with clinical tests, that depend on age; many such tests known to pediatricians and child development experts. For babies and infants, development screening and neurodevelopment tests exist such as for example, BSID—Bayley Scales of Infant Development, Brazelton Neonatal Behavioral Assessment Scale, NEPSY—A Developmental NEuroPSYchological Assessment and Griffiths Mental Development Scales. For pre-school and/or school children tests for cognitive abilities include PPVT (Peabody Picture Vocabulary Test), TONI-2 (Test of Nonverbal Intelligence-2), WPPSI (Wechsler Preschool and Primary Scales of Intelligence), and CPM (Raven's Coloured Progressive Matrices).
It is known that nutrition plays an important role in neuronal maturation in the brain (reviewed in [Huppi, P. S. (2008); Nutrition for the Brain, Pediatric Research, 63(3): 229-231]). Specifically, clinical studies have shown that essential fatty acids, are crucial to ensure foetal and postnatal brain development [Chang, C. Y. et al. (2009); Essential fatty acids and human brain, Acta Neurol. Taiwan, 18(4): 231-41]; [Alessandri, J. M. et al. (2004); Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life, Reprod. Nutr. Dev., 44(6): 509-38].
The consequences of malnutrition can be irreversible and may include poor cognitive development, educability, and thus future economic productivity. [Horton, R; (2008) The Lancet, Vol. 371, Issue 9608, page 179; [Laus, M. F. et al. (2011); Early postnatal protein-calorie malnutrition and cognition: a review of human and animal studies, Int. J. Environ. Res. Public Health., 8(2): 590-612].
It is known that both parental nutrition as well as breast milk of mothers after premature birth provide insufficient nutritional support to the developing brain. Thus, oral interventions are an appropriate way to positively impact on the development of the nervous system, so as to ensure normal development of cognitive function and mental performance in the preterm or term born neonate, infant, toddler, child or young adult or young animal.
There is a need to promote and support the healthy establishment of cognitive function, and/or to reverse retardation and/or to prevent further delay of the establishment of cognitive function at the earliest possible stage during gestation, as well as during the early phases of newborn life, when the nervous system is rapidly maturing.
Because the central nervous system and, in particular, parts of the cortex and the hippocampus, develop until adolescence/early adulthood (20 years), there is a need to provide nutritional support for the healthy establishment and development of cognitive function throughout the young life of the child until adolescence. In particular, there is a need to prevent or treat the severity of disorders such as impaired learning ability, loss of, or poor development of higher reasoning, abnormally low concentration, including Attention Deficit Hyperactivity Disorder (ADHD), delay in language development, memory and executive function problems, abnormally low intelligence, and thus, abnormally low mental performance in children from birth to early adulthood (20 years old).
There is a need to provide a treatment of these disorders in patients who have been diagnosed with cognitive function impairment. There is a need to provide a prophylactic treatment for young mammals in the population groups defined above who are at risk of cognitive function impairment. There is a need to provide a composition to be used in such treatments.
There is a need to positively impact neuronal maturation in the brain of young mammals, in particular, the structures of the brain associated with cognitive function. Specifically, there is a need to positively impact neuronal growth, survival, plasticity and differentiation. There is a need to positively impact signal transmission in the brain by supporting myelination.
There is a need to provide such treatment, prophylactic treatment or such related composition in a form that is well accepted by the subject population, in particular those of in these populations that are the most fragile or the most in need. There is a further need to not induce disadvantages, side-effects or negatives in such population. There is a need to provide such solutions to the subject populations in the most simple and most cost-effective way.
The present invention applies to all mammals, including animals and humans.